We have new data showing marked tachycardic and hypertensive responses in male mice switched to cages previously occupied by a different male mouse. The pressor, but not the heart rate or activity, effect of this stress is blunted significantly in interleukin-6 (IL-6) knockout mice. We also have new evidence that shows considerable acute and chronic interaction with the sympathetic and renin-angiotensin systems. This project will test the hypothesis that interleukin-6 (IL-6) plays a major role in sympathetic- and angiotensin II-mediated hypertensive responses to psychosocial stress. The Specific Aims are: 1) to test the hypothesis that IL-6 contributes significantly to the acute pressor response to psychological stress. We will use acute cage-switch stress testing in mice to determine whether a) IL-6 knockout (KO) mice have a blunted increase in blood pressure compared to wild-type (WT) mice; b) TNF-a knockout mice have an attenuated pressor response to cage switch, similar to IL-6 knockout; c) restoring IL-6 in KO mice will restore a normal pressor response to psychological stress; d) the pressor response in WT mice injected with IL-6 antibody will mimic the response in IL-6 KO mice. 2) to determine the role of IL-6 in mediating the bi-directional blood pressure interactions between acute psychosocial stress and chronic hypertension. These experiments will determine whether: a) cage-switch stress causes IL-6-dependent hypertension after the initial pressor response has subsided; b) Angll hypertension increases the dependence of psychosocial stress-induced pressor responses on IL-6; c) repeated cage-switch stress testing causes a greater increase in MAP over time in WT versus KO mice. 3) to test the hypothesis that the sympathetic nervous system initiates IL-6-dependent blood pressure increases during acute stress, directly and through stimulation of the renin-angiotensin system. We will study the blood pressure increase during acute cage-switch stress testing and test the hypotheses that: a) a-/b-adrenergic receptor blockade will block the pressor response more in WT than in IL-6 KO mice; b) Angll receptor blockade will block the pressor response more in WT compared to IL-6 KO mice; c) the effect of adrenergic blockade will be blunted in mice with the Angll system clamped at normal.